Topical capecitabine for the treatment of hyperproliferative skin conditions

ABSTRACT

The present invention relates to a novel and unexpected method of using topical Capecitabine composition to obtain therapeutically effective amounts of fluorouracil (FU) within the skin of a subject afflicted with hyperproliferative or inflammatory skin condition. The method comprising topically administering a pharmaceutical composition comprising Capecitabine or a hydrate or solvate thereof to the affected area of the skin of the subject, to form therapeutically effective amounts of FU within the skin.

BACKGROUND OF THE INVENTION

Maintenance of homeostasis in the skin requires a delicate balance amongproliferation, differentiation, and apoptosis. Many common diseases ofthe skin, e.g., epidermis, such as actinic keratosis, psoriasis,squamous cell carcinoma, keratoacanthoma, and warts, are characterizedby localized abnormal cell proliferation and growth.

Actinic keratosis (AK), also referred to as solar keratosis, is a skindisorder in which hyperplastic epidermal lesions develop in response toexcessive and chronic exposure to ultraviolet (UV) radiation, such assunlight. AK incidence is rising worldwide as a result of theprogressive aging of populations and an increase in lifetime cumulativeexposure to UV radiation. It has become a significant health care issueand is one of the most common reasons for consulting a dermatologist.

AK cutaneous lesions are pre-cancerous, as the majority of squamous cellcarcinomas (SCCs) progress from preexisting AK and untreated lesionshave up to a 20% risk of progression to squamous cell carcinoma.Furthermore, they are also accounted as a risk factor for melanoma andnonmelanoma skin cancer (NMSC). However, it is still not possible topredict which AK lesions will develop into SCC. Therefore, the lesionsrequire careful evaluation and effective early treatment.

Basal cell carcinoma (BCC) is the most common malignant neoplasm foundin human populations and constitutes roughly 80% of all non-melanomaskin cancers. BCC tumors have a characteristic slow progression andmetastasis is extremely rare. Nonetheless, it can be very destructiveand disfiguring since the invasive growth pattern can destroy cartilageand bone and reach vital structures (major vessels or CNS) with a fatalcourse. Thus early recognition is especially important.

Current treatments for AK and BCC include a variety of surgical andnon-surgical therapies. Surgical therapies include chemical peeling,dermabrasion, curettage and electrosurgery, cryosurgery and lasersurgery. Photodynamic therapy with photosensitizing agents such as,aminolevulinic acid hydrochloride (ALA) or hematoporphyrin is alsoavailable. These treatments can lead to unnecessary adverse effects inthe surrounding tissue such as scar formation or other cosmeticallydisfiguring events.

In addition to the surgical therapies for AK and BCC, there are severalFDA-approved drugs for treatment of AK and BCC. Obviously, the use of adrug in a topical manner to treat a skin disease state is desirable inthat only a locally effective concentration of the drug needs to beattained in the skin. This is of great importance with systemicanti-cancer treatments which necessarily result in exposure ofsusceptible healthy cells, in non-target parts of the body, to cytotoxicchemicals and also have lower patient acceptance.

Topical FDA-approved drugs for AK and BCC are currently in the market,such as fluorouracil (e.g., 5-fluorouracil), Imiquimod and Ingenolmebutate.

Fluorouracil (FU), e.g., 5-fluorouracil, delivered topically is widelyused to treat actinic or solar keratoses as well as superficial basalcell carcinomas. It is a fluorinated nucleoside known to be useful as anantineoplastic antimetabolite, affecting both DNA and RNA and leading tocell death.

Topical fluorouracil exists in solution formulations containing 2%, and5% by weight fluorouracil, and cream formulations containing 1%, 4% and5% by weight fluorouracil. However, these formulations, whilebeneficial, are irritating to the skin, causing side effects such asburning, allergic contact dermatitis, erythema, pain, pruritus, andulceration. A cream formulation of 0.5% FU in which a part of thefluorouracil is incorporated into porous microspheres was approved bythe FDA under the brand name Carac™. Although found to be lessirritating than the previous formulations, irritation at the applicationsite was reported in more than 90% of the patients who participated inthe phase III clinical trials reported to the FDA, including symptoms oferythema, redness, dryness, burning, pain, erosion (loss of the upperlayer of skin), and swelling.

The local skin reactions after the application of FU, imiquimod oringenol mebutate, may be of such intensity that patients may requirerest periods from treatment, or prematurely discontinue treatment beforefull clearance is achieved. Thus, there is still need for lessirritating topical treatments for AK and BCC.

Furthermore, many of the current treatments for AK and BCC, althoughsomewhat effective, can severely damage adjacent, healthy skin due tothe fact that, in part, it is very difficult to differentiate betweendiseased and healthy skin tissue. As such, it is possible to either missan affected, pre-cancerous area as well as to harm healthy skin,adjacent to the lesion.

Another drawback regarding the current topical medications for AK andBCC is their handling during preparation and application. Efudex™instructions for example include that it should be applied with anonmetal applicator or suitable glove, and if applied with fingers, thehands should be washed immediately. Carac™ instruction to the patient isto avoid contact with the eyes, eyelids, nostrils, and mouth and to washhands immediately after applying the cream.

The barrier to absorption of topically applied drugs is the stratumcorneum which comprises a dead, dry (5-10% H₂O), compactkeratin-containing material. Moreover, AK is associated with tough,hardened areas of skin, therefore necessitate the penetration of theactive ingredients through the stratum corneum in order to effectivelytreat the skin lesions.

U.S. Pat. No. 5,610,160 discloses a methylcarbonyl prodrug of FU fortopical application having enhanced permeability across the externalskin layer compared to FU. The FU prodrug is converted to FU bynon-specific hydrolysis after the delivery to the skin. However, theconversion into FU is not specific to cancerous cells only.

There remains therefore, a need for a topical treatment forhyperproliferative skin conditions that will effectively andspecifically target the pre-cancerous or cancerous skin cells whileensuring that adjacent healthy skin tissue is preserved, thus reducingskin irritation and damage to normal skin cells, improving patientcompliance and increasing treatment success.

BRIEF SUMMARY OF THE INVENTION

The present disclosure is directed to a method of treating ahyperproliferative skin condition or inflammatory skin condition in asubject in need thereof, the method comprising topically administering apharmaceutical composition comprising an effective amount of atherapeutic agent selected from Capecitabine, 5′-deoxy fluorocytidine(5′DFCR), 5′-deoxy-5-fluorouridine (5′DFUR), or combinations thereof tothe affected area of the skin of the subject, thereby treating thecondition.

In some embodiments, the topical administration of the pharmaceuticalcomposition comprising an effective amount of the therapeutic agentforms a therapeutically effective amounts of fluorouracil (FU) withinthe skin of the subject to treat the hyperproliferative or inflammatoryskin condition.

In some embodiments, the therapeutic agent is Capecitabine. In someembodiments, the therapeutic agent is 5′-deoxy-5-fluorocytidine(5′DFCR). In some embodiments, the therapeutic agent is5′-deoxy-5-fluorouridine (5′DFUR).

In some embodiments, the hyperproliferative skin condition is apre-cancerous or cancerous skin condition. In some embodiments, thepre-cancerous skin condition is actinic keratosis. In some embodiments,the cancerous skin condition is selected from basal cell carcinoma,squamous cell carcinoma and melanoma.

In some embodiments, the hyperproliferative skin conditions can benon-cancerous inflammatory skin conditions, such as psoriasis, seborrheaand ichthyosis.

In some embodiments, the effective amount of therapeutic agent in thecomposition is from about 0.1% to about 15% by weight of thecomposition. In some embodiments, the effective amount of Capecitabinein the composition is from about 0.1% to about 15% by weight of thecomposition. In some embodiments, the effective amount of Capecitabinein the composition is from about 1% to about 10% by weight of thecomposition.

In some embodiments, the method further comprising topicallyadministering at least one additional pharmaceutical agent useful fortreating a hyperproliferative or inflammatory skin condition. In someembodiments, the therapeutic agent and the at least one additionalpharmaceutical agent are in the same pharmaceutical composition. In someembodiments, the at least one additional pharmaceutical agent isselected from diclofenac, imiquimod, ingenol mebutate or other ingenolderivatives, uracil, 5-chloro-2,4-dihydroxypyridine (CDHP), eniluracil,photosensitizing agents, retinoids, interferons, α-hydroxy acids, andcaustic agents.

In some embodiments, the topical administration is performed with anadditional therapeutic treatment known to be effective in ahyperproliferative skin condition or an inflammatory skin condition. Insome embodiments, the additional therapeutic treatment is selected fromcryosurgery, curettage and desiccation, excision, chemical peeling,dermabrasion, laser surgery and photodynamic therapy.

In some embodiments, the disclosure is directed to a topicalpharmaceutical composition comprising an effective amount of atherapeutic agent selected from Capecitabine, 5′-deoxy-5-fluorocytidine(5′DFCR), 5′-deoxy-5-fluorouridine (5′DFUR), or combinations thereof ina pharmaceutically acceptable carrier, wherein the composition issuitable for topical administration and forms a therapeuticallyeffective amounts of FU within the skin.

In some embodiments, the therapeutic agent in the composition isCapecitabine. In some embodiments, therapeutic agent in the compositionis 5′-deoxy-5-fluorocytidine (5′DFCR). In some embodiments, thetherapeutic agent in the composition is 5′-deoxy-5-fluorouridine(5′DFUR).

In some embodiments, the composition is a solid topical dosage form, asemisolid topical dosage form or a liquid topical dosage form. In someembodiments, the dosage form is in the form of dusting powder, paste,solution, ointment, cream, lotion, gel, spray, liniment or foam.

In some embodiments, the pharmaceutically acceptable carrier is one ormore of a gelling agent, a solvent, a viscosifier, a penetrationenhancer, a preservative, a thickening agent, an antioxidant, achelating agent, an active ingredient stabilizer, an active ingredientsolubilizer and/or a cosmetic ingredient.

In some embodiments, the composition comprises from about 1% to about10% of the therapeutic agent by weight. In some embodiments, thecomposition comprises from about 0.1% to about 15% by weightCapecitabine. In some embodiments, the composition comprises from about1% to about 10% Capecitabine by weight.

In some embodiments, the composition is suitable for application to asubject having a pre-cancerous or cancerous hyperproliferative skincondition. In some embodiments, the pre-cancerous skin condition isactinic keratosis. In some embodiments, cancerous skin condition isbasal cell carcinoma.

In some embodiments, the composition further comprises at least oneadditional pharmaceutical agent useful for treating hyperproliferativeskin conditions. In some embodiments, the at least one additionalpharmaceutical agent is selected from diclofenac, imiquimod, ingenolmebutate or other ingenol derivatives, uracil,5-chloro-2,4-dihydroxypyridine (CDHP), eniluracil, photosensitizingagents, retinoids, interferons, α-hydroxy acids, and caustic agents.

In some embodiments, the composition is used in conjunction with atleast one therapeutic treatment known to be effective inhyperproliferative or inflammatory skin conditions. In some embodiments,the therapeutic treatment is selected from cryosurgery, curettage anddesiccation, excision, chemical peeling, dermabrasion, laser surgery andphotodynamic therapy.

In some embodiments, the disclosure is directed to a method of providingfluorouracil (FU) to a subject in need thereof, the method comprisingtopically administering a pharmaceutical composition comprising aneffective amount of a therapeutic agent selected from Capecitabine,5′-deoxy-5-fluorocytidine (5′DFCR), 5′-deoxy-5-fluorouridine (5′DFUR),or combinations thereof to the skin of the subject, whereby thetherapeutic agent is converted to FU in the skin.

In some embodiments, the disclosure is directed to a method of reducingadverse effects to fluorouracil (FU) in a subject with ahyperproliferative skin condition or inflammatory skin condition, themethod comprising topically administering a pharmaceutical compositioncomprising an effective amount of a therapeutic agent selected fromCapecitabine, 5′-deoxy-5-fluorocytidine (5′DFCR),5′-deoxy-5-fluorouridine (5′DFUR), or combinations thereof to the skinof the subject, whereby the therapeutic agent is converted to FU inhyperproliferating skin cells at a greater rate thannon-hyperproliferating skin cells, thereby reducing adverse effects.

In some embodiments, the disclosure is directed to a method ofdecreasing adverse effects of administration of fluorouracil (FU), themethod comprising topically administering a pharmaceutical compositioncomprising an effective amount of a therapeutic agent selected fromCapecitabine, 5′-deoxy-5-fluorocytidine (5′DFCR),5′-deoxy-5-fluorouridine (5′DFUR), or combinations thereof to the skinof the subject, whereby the therapeutic agent is converted to FU in theskin after administration, whereby adverse effects are decreased by areduction of exposure to FU during administration.

In some embodiments, the disclosure is a method of reducing unintendedexposure to fluorouracil (FU) during administration of FU to a subject,the method comprising topically administering a pharmaceuticalcomposition comprising an effective amount of a therapeutic agentselected from Capecitabine, 5′-deoxy-5-fluorocytidine (5′DFCR),5′-deoxy-5-fluorouridine (5′DFUR), or combinations thereof to the skinof the subject, whereby the therapeutic agent is converted to FU in theskin, whereby unintended exposure does not occur during theadministration process.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic representation of the enzymatic degradationpathway of Capecitabine to 5-fluorouracil.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel and unexpected use ofCapecitabine, a FU prodrug, in the treatment of hyperproliferative skinconditions following topical application. Capecitabine is anFDA-approved oral drug under the Trade name of Xeloda™ used for thetreatment of metastatic colorectal cancer, metastatic breast cancer andadjuvant colon cancer. When taken orally, the Capecitabine pro-drug ismetabolized to FU via a three-step enzymatic process, in which the thirdstep is localized predominantly in the tumor tissue.

The present invention relates to a novel and unexpected method of usingtopical Capecitabine composition to obtain therapeutically effectiveamounts of fluorouracil (FU) within the skin of a subject afflicted withhyperproliferative or inflammatory skin condition, the method comprisingtopically administering a pharmaceutical composition comprising aneffective amount of Capecitabine or a hydrate or solvate thereof to theaffected area of the skin of the subject, to form therapeuticallyeffective amounts of FU within the skin.

Unexpectedly, the inventors of the present invention have discoveredthat FU can be formed in therapeutically effective amounts in the skinfollowing topical administration of the pro-drug Capecitabine (and itsenzymatically metabolized forms) specifically in hyperproliferating skintissue such as actinic keratosis skin. Surprisingly, topicaladministration of Capecitabine allows the conversion of Capecitabine toFU in hyperproliferating skin, while very low FU was formed in healthyskin. Thus, the inventors of the present invention have discovered thattopical Capecitabine is effective in the treatment of hyperproliferativeskin conditions, including pre-cancerous and cancerous skin conditions.The in situ formation of FU specifically in hyperproliferating skin ishighly advantageous since it might reduce the damage of FU to normalskin cells in the surrounding healthy tissue and decrease the irritationand local skin reactions following topical administration.

The use of topical Capecitabine compositions of the present inventionwould improve patient safety during handling and patient compliance,prevents prematurely discontinuation of treatment and hence increasestreatment success over that of the standard FU treatment. In someembodiments, the use of topical Capecitabine can prolong the treatmentduration by preventing premature discontinuation of treatment. Moreover,Capecitabine is metabolized into FU through a specific cascade ofenzymatic processes, enabling selective FU exposure predominantly inpre-cancerous and cancerous cells. This cascade of enzymatic processesis outlined in FIG. 1 . Generally speaking, Capecitabine is converted to5′-deoxy-5-fluorocytidine (5′DFCR) by carboxylesterase (CES). 5′DFCR isthen converted to 5′-deoxy-5-fluorouridine (5′DFUR) by cytidinedeaminase. 5′DFUR is converted to 5-fluorouracil by thymidinephosphorylase (TP). This enzymatic degradation allows administration ofone or more FU-precursors to effect a targeted delivery of apharmacologically effective amount of FU specifically into pre-cancerousand cancerous cells.

Drug penetration through the stratum corneum is an obstacle in thedevelopment of any topical treatment. Moreover, AK is associated withtough, hardened areas of skin, therefore necessitate the penetration ofthe active ingredients into the epidermis skin layer. Being a morelipophilic compound than FU, Capecitabine exhibits better skinpenetration than FU, leading to higher levels of the drug in the skin.

Another advantage of using the Capecitabine prodrug and not FU fortopical treatment is its lower toxicity during handling. Being lesshazardous, the topical use of Capecitabine may increase the safetyduring handling and patient compliance, and also may reduce theprecautions needed during the manufacturing process.

In one embodiment, the present invention relates to the use of topicalCapecitabine compositions for the treatment of hyperproliferative skinconditions.

In another embodiment, the present invention relates to the use oftopical Capecitabine compositions for the treatment of inflammatory skinconditions. In one embodiment, the inflammatory skin conditions areselected from acne, rosacea, atopic dermatitis, Vitiligo and Alopeciaareata.

According to a preferred embodiment of the present invention, thehyperproliferative skin conditions include pre-cancerous or cancerousskin conditions.

In one embodiment, the hyperproliferative skin conditions arepre-cancerous skin conditions, such as but not limited to actinickeratoses.

In an additional embodiment, the hyperproliferative skin conditions arecancerous skin conditions, such as but not limited to basal cellcarcinoma, squamous cell carcinoma and melanoma.

In yet another embodiment, the hyperproliferative skin conditions can benon-cancerous skin conditions, such as psoriasis, seborrhea andichthyosis.

Accordingly, the present invention provides a pharmaceutical compositionin a dosage form suitable for topical administration to a human in needthereof, comprising a pharmacologically effective amount of Capecitabinein a pharmaceutically accepted carrier.

In one embodiment, the topical Capecitabine composition comprises fromabout 0.1% to about 15% by weight Capecitabine in a pharmaceuticallyaccepted carrier, more preferably the topical Capecitabine compositioncomprises from about 1% to about 10% Capecitabine.

In one embodiment, the topical Capecitabine composition is in the formof solution, ointment, cream, lotion, gel, spray or foam.

In another embodiment, the present invention provides a method oftreating hyperproliferative or inflammatory skin conditions, in asubject in need thereof, the method comprising topically administering atherapeutically effective amount of a pharmaceutical composition ofCapecitabine to the affected area of the skin.

In one embodiment, the pre-cancerous or cancerous skin condition isactinic keratosis, basal cell carcinoma, squamous cell carcinoma ormelanoma.

In yet another embodiment, the hyperproliferative skin conditions can benon-cancerous skin conditions, such as psoriasis, seborrhea andichthyosis.

In one embodiment, the inflammatory skin conditions are selected fromacne, rosacea, atopic dermatitis, Vitiligo and Alopecia areata.

In a preferred embodiment, the pre-cancerous skin condition is actinickeratosis and the cancerous skin condition is basal cell carcinoma.

Another aspect of the present invention is a combination of Capecitabinetopical treatment with other therapeutic treatments effective forhyperproliferative skin conditions.

In one embodiment, the present invention provides a method of treating ahyperproliferative or inflammatory skin condition, selected frompre-cancerous, cancerous skin condition and inflammatory skin condition,in a subject in need thereof, the method comprising topically applying apharmaceutical composition comprising an effective amount ofCapecitabine or a hydrate or solvate thereof to the affected area of theskin of the subject.

In another embodiment, the present invention provides a topicalpharmaceutical topical composition comprising an effective amount ofCapecitabine or a hydrate or solvate thereof in a pharmaceuticallyaccepted carrier, wherein the composition is topically applied on theskin of a subject afflicted with hyperproliferative or inflammatory skincondition, to form therapeutically effective amounts of FU within theskin.

In one embodiment, the present invention relates to a method of usingtopical Capecitabine composition to obtain therapeutically effectiveamounts of fluorouracil (FU) within the skin of a subject afflicted withhyperproliferative or inflammatory skin condition, the method comprisingtopically administering a pharmaceutical composition comprising aneffective amount of Capecitabine or a hydrate or solvate thereof to theaffected area of the skin of the subject, to form therapeuticallyeffective amounts of FU within the skin.

In another embodiment, the present invention relates to Capecitabinetopical compositions and to a method of treating a hyperproliferative orinflammatory skin condition in a subject in need thereof, comprisingtopically applying a pharmaceutical composition comprising an effectiveamount of Capecitabine to the affected area of the skin of the subject.

According to one embodiment of the invention, the hyperproliferativeskin conditions are pre-cancerous or cancerous skin conditions.

According to yet another embodiment, the hyperproliferative skinconditions can be non-cancerous skin conditions.

According to specific embodiments, the hyperproliferative skinconditions to be treated according to the principles of the presentinvention, include, but are not limited to, actinic keratoses,psoriasis, common warts, genital warts, keratoacanthoma, seborrheickeratosis, seborrhea, ichthyosis, basal cell carcinoma, squamous cellcarcinoma and melanoma. Each possibility represents a separateembodiment of the invention.

In one embodiment, the hyperproliferative skin conditions arepre-cancerous skin conditions, such as but not limited to actinickeratoses.

In particular embodiments, actinic keratoses conditions are selectedfrom the group consisting of actinic keratosis (also called solarkeratosis), hypertrophic actinic keratosis, Bowenoid actinic keratosis,arsenical keratosis, hydrocarbon keratosis, thermal keratosis, radiationkeratosis, chronic scar keratosis, viral keratosis, actinic cheilitis,Bowen's disease, erythroplaquia of queyrat, oral erythroplaquia,leukoplakia and intraepidermal epithelioma.

In an additional embodiment, the hyperproliferative skin conditions arecancerous skin conditions, such as but not limited to basal cellcarcinoma, squamous cell carcinoma and melanoma.

In a preferred embodiment, the pre-cancerous skin condition is actinickeratosis and the cancerous skin condition is basal cell carcinoma.

The inventors of the present invention have surprisingly discovered thatthe prodrug capecitabine is effectively converted into FU in skin cells,predominantly in hyperproliferating skin cells, more specifically inpre-cancerous and cancerous skin cells, and particularly in skin cellsaffected with AK and BCC.

According to various embodiments of the present invention, thepercentage of Capecitabine that is converted to FU in the skin followingtopical application is at least 0.1%, at least 3%, at least 5%, at least8%, at least 10%, at least 20%, at least 30%, at least 40%, at least50%, at least 60%, at least 70%, at least 80% or at least 90% of theapplied dose of Capecitabine.

In one embodiment, the present invention provides a pharmaceuticalcomposition in a dosage form suitable for topical administration to ahuman in need thereof comprising a pharmacologically effective amount ofCapecitabine in a pharmaceutically accepted carrier.

The precise amount of Capecitabine effective for treating thehyperproliferative skin conditions will vary according to factors knownin the art including, but not limited to, the physical and chemicalnature of the particular compound being administered; the extent ofCapecitabine metabolism to FU; the physical and chemical nature of theformulation; the size, location, and histological type of the lesion;and the intended dosing regimen.

In one embodiment, the topical composition comprises from about 0.01% toabout 15% by weight Capecitabine in a pharmaceutically accepted carrier.

In another embodiment of the invention, the topical Capecitabinecomposition comprises from about 0.1% to about 10% Capecitabine byweight.

In a preferred embodiment, the topical composition comprises from about1% to about 10% Capecitabine by weight.

According to one embodiment, the Capecitabine can be present in thecomposition as a hydrate or solvate thereof.

Pharmaceutical compositions include any formulations which arepharmaceutically acceptable for topical delivery of the compounds of theinvention. The choice of topical formulation will depend on severalfactors, including the physiochemical characteristics of the particularcompound(s) of the invention and of other excipients present, theirstability in the formulation, available manufacturing equipment, andcost constraints.

The Capecitabine compositions of the present invention can be in anysuitable carrier known in the art and is pharmaceutically acceptable fortopical delivery including, but not limited to, solution, ointment,cream, lotion, gel, spray or foam.

In some embodiments, the pharmaceutically acceptable carrier is one ormore of a water in oil emulsion, an adsorbing agent, an emulsifyingagent, a solvent (e.g., liquid or semi-solid solvent), a stabilizer, apermeation enhancer, a lipophilic material, e.g., an oil, an emollient,a hydrocolloidal agent, or a gelling agent. Suitable pharmaceuticallyacceptable carrier suitable for topical administration are known in theart, e.g., Garg et al., Comprehensive review on additives of topicaldosage forms for drug delivery,” Drug Deliv, 22(8):969-987 (2015).

In a preferred embodiment, the compositions of the present invention arein the form of a hydroalcoholic gel, a cream or an ointment.

Preparation of suitable formulations is within the skill of those in theart, and suitable excipients for inclusion in any such formulationinclude, for example, gelling agents, solvents, viscosifiers,penetration enhancers, preservatives, thickening agents, antioxidants,chelating agents, and cosmetic ingredients, such as fragrances andcolourings.

Suitable solubilizing agents include, but are not limited to, ethanol,isopropanol, benzyl alcohol, cetyl alcohol, dimthylsulfoxide (DMSO),polyethylene glycols (PEGs), propylene glycol, hexylene glycol, glyceroland diethylene glycol monoethyl ether. In some embodiments, the solventsmay include oils and waxes such as paraffins, mineral oil, coconut oil,castor oil, and medium chain triglycerides. In other embodiments, thesolubilizing agents include cyclodextrins, such as β-cyclodextrin (BCD)or hydroxypropyl-β-cyclodextrin (HPBCD). The solubilizing agents can beincluded as a single solvent or a combination of more than onesolubilizing agent.

Suitable gelling agents include, but are not limited to, water solublecellulose derived polymers, such as hydroxyalkyl cellulose polymers(e.g. hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and hydroxypropylmethylcellulose), carboxymethylcellulose, methylhydroxyethyl cellulose and methyl cellulose, carbomers(e.g. carbopol); xanthan and carrageenans. The gelling agent may beadded in any suitable amount, such as between about 1 to about 5% (w/w).In one embodiment, the gelling agents are carbomers, including, but arenot limited to, carbomer 910, 934P (Carbopol® 934P), 940, 941, 974P(Carbopol® 974P), 980 (Carbopol® 980) and 981.

Suitable emulsifiers for use in the compositions of the presentinvention include, but are not limited to, glycine soja protein, sodiumlauroyl lactylate, polyglyceryl-4diisostearate-polyhydroxystearate-sebacate, behentrimoniummethosulfate-cetearyl alcohol, non-ionic emulsifiers like emulsifyingwax, polyoxyethylene oleyl ether, PEG-40 stearate, carbomer,polysorbates and sorbitan esters, cetostearyl alcohol (cetearylalcohol), ceteareth-12, ceteareth-20, ceteareth-25, ceteareth-30,ceteareth alcohol, Ceteth-20, oleic acid, oleyl alcohol, glycerylstearate, PEG-75 stearate, PEG-100 stearate, and PEG-100 stearate,ceramide 2, ceramide 3, stearic acid, cholesterol, laureth-12,steareth-2, and steareth-20, or combinations/mixtures thereof, as wellas cationic emulsifiers like stearamidopropyl dimethylamine andbehentrimonium methosulfate, or combinations/mixtures thereof.

Suitable penetration enhancers include, but are not limited to, polyolsand esters, including polyethylene glycol, polyethylene glycolmonolaurate, and butanediol; sulfoxides, including dimethylsulfoxide(DMSO) and decylmethylsulfoxide; ethers, including diethylene glycolmonoethyl ether (e.g., Transcutol. P) and diethylene glycol monomethylether; fatty acids, including lauric acid, oleic acid, and valeric acid;fatty acid esters, including isopropyl myristate, isopropyl palmitate,methyl propionate, and ethyl oleate; nitrogenous compounds includingurea, dimethyl acetamide, dimethylformamide 2-pyrrolidone, ethanolamine,methyl-2-pyrrolidone, diethanolamine, and triethanolamine; terpenes;alkanones; organic acids, including salicylic acid, citric acid, andsuccinic acid; and any mixtures thereof.

Suitable thickening agents include polyqueternium-10, Sepino™ P600, PEG120 methyl glucose dioleate, sodium alginate, gum arabic, cellulosederivatives, such as methylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, hydroxylpropylcellulose orhydroxypropylmethylcellulose, guar gum or its derivatives, xanthan gum,or combinations thereof.

Suitable preservatives will be apparent to those skilled in the art, andinclude the parabens, such as methylparaben, propylparaben,isopropylparaben, butylparaben, and isobutylparaben, and their saltssuch as sodium butylparaben, benzoic acid and its salts and esters,benzyl alcohol, urea derivatives such as diazolidinyl urea,imidazolidinyl urea, and DMDM hydantoin, sorbic acid and its salts, andthe like. Preservatives employed solely for that purpose will generallyform 1% (w/w) or less of the final topical formulation. Preferably, thepreservatives are a combination of parabens, such as methylparaben andpropylparaben.

Examples of water-soluble antioxidants include ascorbic acid and itssalts, such as sodium ascorbate, isoascorbic acid and its salts, sodiumsulfite, sodium metabisulfite, sodium thiosulfite, thiols such asthioglycerol, thiosorbitol, thiourea, thioglycolic acid, and cysteine,and the like. Examples of oil-soluble antioxidants include BHT(butylated hydroxytoluene), BHA (butylated hydroxyanisole), tocopherol(vitamin E), tocopheryl acetate, ascorbyl palmitate, hydroquinone,di-t-butylhydroquinone, propyl gallate, and the like. Preferably, theantioxidant is BHT.

Optional chelating agents include, but are not limited to, EDTA(ethylenediaminetetraacetic acid) and its salts, for example disodiumEDTA, trisodium NTA, etidronic acid and its salts, sodiumdihydroxyethylglycinate, citric acid and its salts, and the like.Preferably, the chelating agent is EDTA or its salts.

Suitable colorants and fragrances will be a matter of choice, providedonly that they should be compatible with the formulation.

Some of the excipient substances described above can have more than onefunction in a formulation. For example, a substance can be both asolvent and a penetration enhancer, or both an emollient and apenetration enhancer. The categorizations of materials described aboveare not to be construed as limiting or restricting in any manner.

In some embodiments, the present invention further relates toCapecitabine topical compositions wherein, the compositions are stablefor a period of at least 6 months at accelerated storage conditions. Insome embodiments, the compositions are stable for a period of at least12 months at room temperature conditions.

In some embodiments, the term “stable” as used herein refers to physicalstability and/or chemical stability of the active agent in a topicalcomposition, wherein changes in the drug assay values and/or impuritiescontent are less than about 5%, during stability study of thecomposition at 25° C. and 60% relative humidity (referred as “RTconditions”), or 40° C. and 75% relative humidity (referred as“accelerated storage conditions”), for durations such as 1, 3, 6, 12,18, or 24 months.

The topical Capecitabine compositions of the present invention exhibiteffective skin penetration to the affected skin area. According to someembodiments of the present invention, at least 0.01%, at least 0.1%, atleast 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least5%, at least 6%, at least 7%, at least 8%, at least 9% or at least 10%of the applied Capecitabine dose penetrates into the skin. In oneembodiment, at least 0.5%, at least 1%, at least 2%, at least 3%, atleast 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least9% or at least 10% of the applied Capecitabine dose penetrates into theepidermis skin layer.

According to additional embodiments, about 0.5% to about 20% of theapplied Capecitabine penetrates into the skin, more preferably, about 1%to about 10% of the applied Capecitabine penetrates into the skin. Inone embodiment, about 0.5% to about 20% of the applied Capecitabinepenetrates into the epidermis skin layer, more preferably, about 1% toabout 10% of the applied Capecitabine penetrates into the epidermis skinlayer.

According to yet additional embodiments, the amount of FU formed withinthe skin after the application of the Capecitabine composition, is fromabout 0.01% to about 90%, or about 0.01% to about 40%, of the appliedCapecitabine dose, more preferably, from about 0.1% to about 20% of theapplied Capecitabine dose, and more preferably, from about 0.1% to about10% of the applied Capecitabine dose. In one embodiment, the amount ofFU found within the epidermis is from about 0.01% to about 20% of theapplied Capecitabine dose, more preferably, from about 0.1% to about 10%of the applied Capecitabine dose.

According to one embodiment, the amount of FU formed within the skinafter the application of the Capecitabine composition, is from about 1μg to about 100,000 μg per 1 cm² of skin tissue. In another embodiment,the amount of FU formed within the skin after the application of theCapecitabine composition, is from about 10 μg to about 10,000 μg per 1cm² of skin tissue. In some embodiments, the amount of FU formed withinthe skin after the application of the Capecitabine composition, is fromabout 0.01 mg to about 100 mg per 1 cm² of skin tissue. In anotherembodiment, the amount of FU formed within the skin after theapplication of the Capecitabine composition, is from about 0.01 mg toabout 10 mg per 1 cm² of skin tissue.

According to one aspect, the present invention provides a method oftreating a pre-cancerous or cancerous skin condition in a subject inneed thereof, the method comprising topically administering atherapeutically effective amount of a pharmaceutical composition ofCapecitabine to the affected area of skin of the subject.

A “therapeutically effective amount” or “therapeutically effectiveamounts” means the amount that, when administered to a subject fortreating a disease, is sufficient to effect treatment for that disease.

The term “treating” or “treatment” of a disease, as used herein,includes preventing the disease from occurring in a subject that may bepredisposed to the disease but does not yet experience or exhibitsymptoms of the disease (prophylactic treatment), inhibiting the disease(slowing or arresting its development), providing relief from thesymptoms or side-effects of the disease (including palliativetreatment), and relieving the disease (causing regression of thedisease).

The term “hyperproliferative”, as used herein, is used to describe acondition with abnormally high proliferation of skin cells, particularlyabnormal proliferation of keratinocytes or melanocytes. This conditioncan be pre-cancerous or cancerous skin condition, as well asnon-cancerous condition.

The term “cancerous”, as used herein, is used to describe a conditionaffected by or showing abnormalities characteristic of cancer.

The term “pre-cancerous”, as used herein, is used to describe acondition that may potentially (or is likely to) become cancer or isassociated with an increased risk of cancer. This term can be replacedby the term premalignant.

The term “non-cancerous”, as used herein, is used to describe a skincondition that is characterized by skin cell hyperproliferation, butcannot be considered as pre-cancerous or cancerous condition asdescribed herein.

According to one embodiment of the invention, the pre-cancerous orcancerous skin condition is selected from actinic keratosis, basal cellcarcinoma, squamous cell carcinoma, and melanoma.

According to a preferred embodiment, the pre-cancerous skin condition isactinic keratosis and the cancerous skin condition is basal cellcarcinoma.

According to one embodiment, the inflammatory skin conditions areselected from acne, rosacea, atopic dermatitis, Vitiligo and Alopeciaareata.

Another aspect of the present invention is a combination of Capecitabinetopical treatment with additional therapeutic treatments known to beeffective in hyperproliferative skin conditions.

According to one embodiment, the additional therapeutic treatment is asurgical procedure such as cryosurgery, curettage and desiccation,excision, chemical peeling, dermabrasion, or laser surgery.

According to another embodiment, the additional therapeutic treatment isphotodynamic therapy with photosensitizing agents such as,aminolevulinic acid hydrochloride (ALA) or hematoporphyrin.

According to another embodiment, Capecitabine topical treatment can becombined with any other additional pharmaceutical agent useful fortreating hyperproliferative skin conditions such as AK or BCC.

In one embodiment, the additional pharmaceutical agents are selectedfrom the group consisting of photosensitizing agents, retinoids,interferons, α-hydroxy acids, and caustic agents. The photosensitizingagent can be, for example, 5-ALA, methoxsalen, porfimer, or verteporfin.The caustic agent can be, for example, trichloroacetic acid or phenol.

In an additional embodiment, the additional pharmaceutical agents areselected from diclofenac, imiquimod and ingenol mebutate or otheringenol derivatives. In yet additional embodiment, the additionalpharmaceutical agents are dihydropyrimidine dehydrogenase (DPD)inhibitors, including uracil, 5-chloro-2,4-dihydroxypyridine (CDHP), oreniluracil.

Having now generally described this invention, the same will be betterunderstood by reference to the following Examples, which are providedherein solely for purposes of illustration only and are not intended tobe limiting of the invention or any embodiment thereof, unless sospecified.

EXAMPLES Example A

To evaluate the conversion of Capecitabine into FU in human skin,Capecitabine can be applied to human skin and the levels of Capecitabineand FU can be measured by analytical methods known in the art. Skinexcised from healthy donors as well as from actinic keratosis patientscan be used for these experiments. The skin can be freshly excised andmaintained in physiological conditions to retain the enzymatic activitywithin the skin.

The penetration/permeation model is a well-validated tool for the studyof percutaneous absorption of topically applied drugs. This model can beused herein to evaluate the conversion of the Capecitabine prodrug intothe FU active drug within the skin by direct measurement of bothCapecitabine and FU levels in the tissue. The model uses freshly excisedhuman skin mounted in specially designed diffusion chambers that allowthe skin to be maintained at a temperature and humidity that match realuse conditions and the application of the drug.

To determine the degree of prodrug conversion into the active drug, bothCapecitabine and FU can be recovered from each skin layer (stratumcorneum, epidermis, and partial dermis) and the receiver compartment andtheir amounts in each skin layer can be determined.

Example 1: Topical Capecitabine Compositions Formulation A:Hydroalcoholic Gel

Ingredient Weight Percent Capecitabine  1.0-15.0 Alcohol 96% USP10.0-40.0 DMSO  5.0-10.0 BHT 0.05-0.1  Methylparaben  0.1-0.3 Propylparaben  0.1-0.5  Carbopol 934P  0.5-2.0  Purified Water q.sHydroxypropyl-β-cyclodextrin  0.5-1.5  (HP-b-Cyclodextrin) Sepineo P600 0.5-4.0 

Formulation B: Hydroalcoholic Gel

Ingredient Weight Percent Capecitabine  1.0-15.0 Alcohol 96% USP10.0-40.0 DMSO  5.0-10.0 BHT 0.05-0.1  Methylparaben  0.1-0.3 Propylparaben  0.1-0.5  Carbopol 934P  0.5-2.0  Purified Water q.sPolyethylene Glycol 400 (PEG-400)  0.5-7.0  Sepineo P600  0.5-4.0 

Formulation C: Oil in Water (Cream)

Ingredient Weight Percent Capecitabine  1.0-15.0 Steareth-2  0.5-5.0 Steareth-20  0.5-5.0  Mineral oil  5.0-30.0 EDTA 0.05-0.1  Methylparaben 0.1-0.3  Propylparaben  0.1-0.5  Isopropyl myristate  1.0-10.0 PurifiedWater q.s Hydroxypropyl-β-cyclodextrin  0.5-2.0  (HP-b-Cyclodextrin)Polyethylene Glycol 400 (PEG-400)  0.5-7.0 

Formulation D: Ointment

Ingredient Weight Percent Capecitabine  1.0-15.0 Super White Petrolatum60.0-80.0 Paraffin NF  1.0-10.0 White wax NF  1.0-10.0 Mineral Oil USP 1.0-10.0 Propylene carbonate NF  1.0-5.0  Polyethylene Glycol 400(PEG-400)  0.5-10.0

Formulation E: Hydroalcoholic Gel

Ingredient Weight Percent Capecitabine  5.00 Alcohol 96% USP 24.00 DMSO 5.00 Sepineo P600  3.00 β-Cyclodextrin  0.50 Methylparaben  0.00Propylparaben  0.00 Purified Water 62.50

Example 2: Evaluation of In Situ Capecitabine Metabolism into FU inViable Fresh Skin Samples Originated from Healthy and Actinic Keratosis(AK) Human Subjects

The penetration/permeation ex vivo model is a well-validated tool forthe study of percutaneous absorption of topically applied drugs. Thismodel was utilized herein to evaluate the conversion of the Capecitabineprodrug into the FU active drug within the skin by direct measurement ofboth Capecitabine and FU levels in the tissue. The model uses freshlyexcised human skin mounted in specially designed diffusion chambers thatallow the skin to be maintained at a temperature and humidity that matchreal use conditions and the application of the drug.

In Situ Capecitabine Metabolism into 5-FU in Healthy Skin:

Experimental Design:

Human skin from a healthy donor was mounted between the donor andreceptor compartment of a vertical diffusion cell. The skin was dosedwith 5% capecitabine formulation (formulation E) or placebo. A verticaldiffusion cell was also prepared to which no formulation was applied toserve as a blank. Receptor solution was added to the receptorcompartment in a fashion such that no air bubbles were present duringtesting. Receptor solution aliquots were collected at 1, 2, 4, 6, 8 and24 h time points and analyzed using a single LC-MS/MS analytical method.Following the final time point collection, residual formulation wasremoved from the surface of the skin and then the skin surface was tapedstriped up to 5 times to remove residual formulation and the top of theskin surface layers (Stratum Corneum). The epidermis was thenheat-separated from the dermis by placing the skin into an incubator at60° C. for 2 min, followed by manually separation using gloved hands.The amount of each drug delivered to epidermis and dermis was thendetermined by LC-MS/MS.

Results: Total Amount of Capecitabine and FU in the Skin and theReceptor Solution:

Extremely low levels of FU were detected in the skin of only onereplicate tested and no FU was detected in the other replicates tested.

Specifically the levels of capecitabine and FU after 24 h, were measuredto be 23,402 ng and 8.07 ng, respectively.

In Situ Capecitabine Metabolism into FU in AK Skin:

Experimental Design:

AK samples from human AK donor were obtained fresh. The LC-MS/MSanalytical method, receptor solution, extraction fluid, and samplingtime points used in the healthy skin were also used with the AK samples.The skin sample was mounted between the donor and receptor compartmentof a vertical diffusion cell. AK skin was mounted onto micro Franz cellwith adapter. Receptor solution (PBS+0.01% Brij) was added to thereceptor compartment of each cell. After about 0.5 h, the skin was dosedwith 5% capecitabine formulation (formulation E) or placebo. Receptorsolution aliquots were collected at 1, 2, 4, 6, 8 and 24 h time pointsand analyzed using a single LC-MS/MS analytical method. Following 24 h,the residual formulation was removed from the surface of the skin. Itwas not possible to separate the epidermis from the dermis of the AKsample (due to the limited size of the samples); therefore the wholetissue (epidermis+dermis) was added to homogeniser tubes. The amount ofcapecitabine and fluorouracil in the skin and receptor solution wasdetermined by LC-MS/MS.

Results: Table 1 below summarizes the amounts (ng) of Capecitabine andFU measured within the AK skin (epidermis and dermis) and in thereceptor solution following 24 hours. Two samples derived from the AKskin were analyzed in parallel. As revealed from the results, asignificant conversion of FU in situ was observed in the AK skin (firstsample exhibited 3.9% conversion out of total amount of Capecitabinepermeating/penetrating and second exhibited 8.5% conversion out of totalamount of Capecitabine permeating/penetrating). These results areunexpected in view of the data obtained in the healthy skin in which thelevel of FU detected within the skin and in the receptor solution wasvery low, if any.

TABLE 1 Total Capecitabine in Total FU in skin % FU of skin and receptorand receptor Capecitabine solution (ng) solution (ng) measured AKdonor-sample 1 62,665 ng 2,465 ng 3.9% AK donor-sample 2 31,586 ng 2,696ng 8.5%

Example 3: Stability of Capecitabine Topical Compositions

The chemical stability of Formulation E was evaluated following 2 weeksin 4° C. The levels of Capecitabine (the Assay results) and the levelsof total impurities were determined during this stability period usingHPLC technique. Table 2 below depicts the stability data obtained.

TABLE 2 ASSAY (%) 110.80% FU Not detected RRT 0.47 Related Compound A0.09 Related Compound B 0.26 RRT 0.68 RRT 1.02 Related Compound C Total(%) 0.35

In some embodiments, the formulations samples can be kept in RTconditions (25° C.) for 24 months and in accelerated storage conditions(40° C.) for 6 months. The levels of Capecitabine (the Assay results)and the levels of total impurities can be determined during thesestability periods using HPLC technique.

Example 4: Skin Penetration Studies

The penetration/permeation model is a well-validated tool for the studyof percutaneous absorption of topically applied drugs. The model usesexcised human skin mounted in specially designed diffusion chambers thatallow the skin to be maintained at a temperature and humidity that matchreal use conditions. The composition is applied to the surface of theskin and the penetration of the compound is measured by monitoring itsrate of appearance in the stratum corneum, epidermis and dermis skinlayers, as well as the receptor solution flowing underneath the skinsamples. Also, this in vitro system has the potential for carefullycontrolling many of the potential variables involved in topicalapplication, like dosing volumes, humidity, temperature, drug stability,skin thickness, etc.

The dermatomed skin is positioned between the two halves of thediffusion cell with the stratum corneum facing the donor compartmentallowing for drug application. The drug concentrations permeating acrosshuman skin and drug penetration within the different skin layers aremeasured.

To determine the penetration of Capecitabine into the skin from thevarious topical compositions (formulations A-E, as listed in Example 1),an in vitro penetration study is conducted using cadaver skin. The totalamount of capecitabine within the skin and receptor cell, as well as theflux rate through the skin to the receptor cell, are analyzed.

In some embodiments, the Capecitabine compositions can be applied tofreshly excised skin from healthy donors as well as from actinickeratosis patients, to allow the measurement of both Capecitabine and5-FU. The total amounts of capecitabine and 5-FU within the skin andreceptor cell can be measured. The 5-FU 5% cream formulation (Efudx™)can be used as a comparative control in order to verify that the skinlevels of 5-FU, achieved from the application of the Capecitabineformulations, are comparable to the clinically approved drug.

Few donors of human skin are used for all tested formulations. Theformulation samples are applied at an infinite dose under occlusion, fora 24-48 hour study. The receptor solution is sampled at specifiedtime-points after application. The flux of the permeation through theskin is calculated for all tested formulations using the slope of thelinear phase of the permeation study.

For the analysis of the skin penetration study, skin extracts areanalyzed with HPLC-UV (HPL-150). The electrical resistance of all skinsamples is confirmed to be >20 kΩ as determined by the TranscutaneousElectrical resistance (TER) measurement which is done at 100 Hz.

Example 5: Effect of Topical Capecitabine Formulations in Mouse AK Model

The efficacy of the topical Capecitabine formulations for the treatmentof AK is evaluated in a mouse model. Mice treated with a UV-B protocolare recognized as the most relevant models since they develop AK-likelesions and SCCs resembling those seen in humans, although differencesexist, such as the thickness of the skin, which is much thinner in micethan in humans. A recent study demonstrated that this mouse model ofUV-B-induced skin lesions is predictive for the identification of noveltherapeutic treatments for both early and advanced stages of the disease(Pillon et al, 2017).

Such model is the Hairless SKH-1 mice exposed to UV-B. These mice do notdevelop fur but contrary to nude mice are still immuno-competent. TheSKH-1 mice (6-8 weeks old, weighing 18-20 g) in individual housing (onemouse/cage) are exposed to UV-B every day for 14-15 weeks. Medium waveUV-B lamps covering from 280 to 320 nm with an energy peak at 312 nm areused, and 10-12 min of UV-B exposure per day is necessary to reach theMED (minimal erythemal dose) in SKH-1 mice. To generate AK lesions andto prevent the risk of skin burn, gradual exposure is performed duringthe first 20 days until the MED is reached and maintained for additional50 to 80 days.

After the UV-exposure period, mice developing actinic keratoses arerandomized into treatment groups, each consisting of mice withobservable skin lesions of comparable number and size. Treated areas aredefined and tattooed to be easily identified. Mice are then treatedtopically with the Capecitabine topical formulation of the invention,vehicle control and FU cream (Efudx™). All treatments and photographingare performed under isoflurane (1.5%) mixed with air/oxygen (80/20) gasanaesthesia.

Histological and immunohistochemical analysis including p53, Ki67 andCD3 expression detection are preformed along with monitoring the mouseskin for lesion cure to evaluate treatment efficacy.

Example 6: Effect of Capecitabine Formulations in Mouse BCC Model

All BCCs have activation of hedgehog signaling pathway as their pivotalmolecular abnormality. Approximately 90% of sporadic BCCs haveloss-of-function mutations in PATCHED 1 (PTCH1), and others haveactivating mutations in the downstream SMOOTHENED (SMO) gene. Based onthis knowledge, several murine models have been developed in which thetransgenic overexpression of activators or the deletion of repressorsdrives skin HH signaling.

One of these models is the Ptch1 heterozygous (Ptch1+/−) mice in whichp53 is deleted specifically from keratin 14 (K14)-expressingkeratinocytes (Ptch1+/−K14-Cre-ER p53 fl/fl). The mice are exposed toionizing (IR) or UV radiation which produces multiple BCC-like tumors inthese mice. Grossly visible tumors are first apparent in irradiated skinafter 4 months of UV exposure in Ptch1+/− mice, and by 11 months of UVexposure more than 80% of the mice develop visible cutaneous tumors(Aszterbaum et al, 1999). The mice are randomized into 3 groups andtreated with the topical Capecitabine formulation, topical FU cream(Efudex™) and vehicle control.

Histological and immunohistochemical analysis including Ki67 analysisand hematoxylin and eosin (H&E) staining to measure BCC size arepreformed along with monitoring the mouse skin to evaluate treatmentefficacy.

It will be appreciated by those skilled in the art that changes could bemade to the exemplary embodiments shown and described above withoutdeparting from the broad inventive concept thereof. It is understood,therefore, that the disclosure herein is not limited to the exemplaryembodiments shown and described, but it is intended to covermodifications within the spirit and scope of the present invention asdefined by the claims. For example, specific features of the exemplaryembodiments may or may not be part of the claimed invention and featuresof the disclosed embodiments may be combined. Unless specifically setforth herein, the terms “a”, “an” and “the” are not limited to oneelement but instead should be read as meaning “at least one.”

It is to be understood that at least some of the descriptions of theinvention have been simplified to focus on elements that are relevantfor a clear understanding of the invention, while eliminating, forpurposes of clarity, other elements that those of ordinary skill in theart will appreciate may also comprise a portion of the invention.However, because such elements are well known in the art, and becausethey do not necessarily facilitate a better understanding of theinvention, a description of such elements is not provided herein.

1-16. (canceled)
 17. A topical pharmaceutical composition comprising aneffective amount of a therapeutic agent selected from Capecitabine,5′-deoxy-5-fluorocytidine (5′DFCR), 5′-deoxy-5-fluorouridine (5′DFUR),or combinations thereof in a pharmaceutically acceptable carrier,wherein the composition is suitable for topical administration and formsa therapeutically effective amounts of FU within the skin.
 18. Thecomposition of claim 17, wherein the therapeutic agent is Capecitabine.19. The composition of claim 17, wherein the therapeutic agent is5′-deoxy-5-fluorocytidine (5′DFCR).
 20. The composition of claim 17,wherein the therapeutic agent is 5′-deoxy-5-fluorouridine (5′DFUR). 21.The topical composition according to claim 17, wherein the compositionis a solid topical dosage form, a semisolid topical dosage form or aliquid topical dosage form.
 22. The topical dosage form according toclaim 21, wherein the dosage form is in the form of dusting powder,paste, solution, ointment, cream, lotion, gel, spray, liniment or foam.23. The topical dosage form according to claim 17, wherein thepharmaceutically acceptable carrier is one or more of a gelling agent, asolvent, a viscosifier, a penetration enhancer, a preservative, athickening agent, an antioxidant, a chelating agent, an activeingredient stabilizer, an active ingredient solubilizer and/or acosmetic ingredient.
 24. The topical composition according to claim 23,comprising from about 1% to about 10% of the therapeutic agent byweight.
 25. The topical composition according to claim 18, comprisingfrom about 0.1% to about 15% by weight Capecitabine.
 26. The topicalcomposition according to claim 25, comprising from about 1% to about 10%Capecitabine by weight.
 27. The topical composition according to claim17, wherein the composition is suitable for application to a subjecthaving a pre-cancerous or cancerous hyperproliferative skin condition.28. The topical composition according to claim 27, wherein thepre-cancerous skin condition is actinic keratosis.
 29. The topicalcomposition according to claim 27, wherein the cancerous skin conditionis basal cell carcinoma.
 30. The topical composition according to claim17, further comprising at least one additional pharmaceutical agentuseful for treating hyperproliferative skin conditions.
 31. The topicalcomposition according to claim 30, wherein the at least one additionalpharmaceutical agent is selected from diclofenac, imiquimod, ingenolmebutate or other ingenol derivatives, uracil,5-chloro-2,4-dihydroxypyridine (CDHP), eniluracil, photosensitizingagents, retinoids, interferons, α-hydroxy acids, and caustic agents. 32.The topical composition according to claim 17, wherein the compositionis used in conjunction with at least one therapeutic treatment known tobe effective in hyperproliferative or inflammatory skin conditions. 33.The topical composition according to claim 32, wherein the therapeutictreatment is selected from cryosurgery, curettage and desiccation,excision, chemical peeling, dermabrasion, laser surgery and photodynamictherapy.
 34. A method of providing fluorouracil (FU) to a subject inneed thereof, the method comprising topically administering apharmaceutical composition comprising an effective amount of atherapeutic agent selected from Capecitabine, 5′-deoxy-5-fluorocytidine(5′DFCR), 5′-deoxy-5-fluorouridine (5′DFUR), or combinations thereof tothe skin of the subject, whereby the therapeutic agent is converted toFU in the skin.
 35. (canceled)
 36. A method of decreasing adverseeffects of administration of fluorouracil (FU), the method comprisingtopically administering a pharmaceutical composition comprising aneffective amount of a therapeutic agent selected from Capecitabine,5′-deoxy-5-fluorocytidine (5′DFCR), 5′-deoxy-5-fluorouridine (5′DFUR),or combinations thereof to the skin of the subject, whereby thetherapeutic agent is converted to FU in the skin after administration,whereby adverse effects are decreased by a reduction of exposure to FUduring administration.
 37. A method of reducing unintended exposure tofluorouracil (FU) during administration of FU to a subject, the methodcomprising topically administering a pharmaceutical compositioncomprising an effective amount of a therapeutic agent selected fromCapecitabine, 5′-deoxy-5-fluorocytidine (5′DFCR),5′-deoxy-5-fluorouridine (5′DFUR), or combinations thereof to the skinof the subject, whereby the therapeutic agent is converted to FU in theskin, whereby unintended exposure does not occur during theadministration process.
 38. (canceled)